Device and method for combining a treatment agent and a gel

ABSTRACT

A method including introducing a treatment agent at a treatment site within a mammalian host; and introducing a bioerodable gel material at the treatment site. An apparatus including a first annular member having a first lumen disposed about a length of the first annular member and a first entry port at a proximal end of the first annular member, and a second annular member coupled to the first annular member having a second lumen disposed about a length of the second annular member and a second entry port at a proximal end of the second annular member, wherein the first annular member and the second annular member are positioned to allow a combining of treatment agents introduced through each annular member at the treatment site.

CROSS-REFERENCE TO RELATED APPLICATION

The application is a divisional of U.S. patent application Ser. No.12/013,286, filed Jan. 11, 2008, which is a divisional of U.S. patentapplication Ser. No. 10/187,007, filed Jun. 28, 2002 (now U.S. Pat. No.7,361,368), and incorporated herein by reference.

BACKGROUND

1. Field

The invention relates to retaining a treatment agent at a treatment sitewith a bioerodable gel.

2. Relevant Art

A major component of morbidity and mortality attributable tocardiovascular disease occurs as a consequence of the partial orcomplete blockage of vessels carrying blood in the coronary and/orperipheral vasculature. When such vessels are partially occluded, lackof blood flow causes ischemia to the muscle tissues supplied by suchvessel, consequently inhibiting muscle contraction and proper function.Total occlusion of blood flow causes necrosis of the muscle tissue.

Blood vessel occlusions are commonly treated by mechanically enhancingblood flow in the affected vessels. Such mechanical enhancements areoften provided by employing surgical techniques that attach natural orsynthetic conduits proximal and distal to the areas of occlusion,thereby providing bypass grafts, or revascularization by various meansto physically enlarge the vascular lumen at the site of occlusion. Theserevascularization procedures involve such devices as balloons,endovascular knives (atherectomy), and endovascular drills. The surgicalapproach is accompanied by significant morbidity and even mortality,while the angioplasty-type processes are complicated by recurrentstenoses in many cases.

In some individuals, blood vessel occlusion is partially compensated bynatural processes, in which new vessels are formed (termed“angiogenesis”) and small vessels are enlarged (termed “arteriogenesis”)to replace the function of the impaired vessels. These new conduits mayfacilitate restoration of blood flow to the deprived tissue, therebyconstituting “natural bypasses” around the occluded vessels. However,some individuals are unable to generate sufficient collateral vessels toadequately compensate for the diminished blood flow caused bycardiovascular disease. Accordingly, it would be desirable to provide amethod and apparatus for delivering agents to help stimulate the naturalprocess of therapeutic angiogenesis to compensate for blood loss due toan occlusion in a coronary and peripheral arteries in order to treatischemia.

In some therapies, e.g., cardiovascular-related, cancer-related, andcertain surgical or minimally-invasive therapies, it may be desirable toinject a treatment agent of or including a sustained release matrixintralumenally, intracardially, or intraventricularly. Unfortunately,however, it is generally difficult to retain the treatment agent at adesired treatment site. In cardiovascular-related therapies, forexample, rarely is greater than 30 percent of the sustained releasematrix retained at the injection site following such therapies. The lossof sustained release matrix generally occurs either during the initialinjection or as a result of backflow from the needle site. The backflowfrom the needle site can occur due to an excessive amount of fluidrequired to deliver the matrix material, or, as the needle is removedfrom the injection site, the site does not seal before matrix materialescapes. The consequences of matrix material escaping can be multifolddepending on the interaction of the matrix and the surrounding blood orfluid.

The loss of matrix material and release can result in inconsistentdosage delivery. The inconsistency in dosage delivery in turn results inthe delivery of the treatment agent that possibly will be at a dosageoutside of the desired or optimum therapeutic window. In the case ofarterial or ventricular treatment sites, a second response would occurif the sustained release matrix has thrombogenic effects, resulting inthe formation of thrombosis that may have severe consequences in thearterial or ventricular region.

What is needed is a technique for retaining a treatment agent, includinga treatment agent of or including a sustained-release matrix at atreatment site.

SUMMARY

A method is disclosed. In one embodiment, the method includesintroducing a treatment agent at a treatment site within a mammalianhost and introducing a bioerodable gel at the treatment site.Representatively, the gel includes a substance that will retain thetreatment agent at a desired treatment site. In one example, thetreatment agent and gel may be introduced as a combination.Alternatively, the treatment agent and gel may be introducedsequentially, such as introducing the gel before and/or after thetreatment agent. The gel may serve, in one aspect, to retain thetreatment agent at the treatment site for a prolonged period of time soas to beneficially stimulate the effect of a treatment agent. Suitabletreatment sites representatively include, but are not limited to, in oraround a blood vessel such as a coronary blood vessel, thoroscopicsurgery sites, orthoscopic surgery sites, and laparoscopic surgerysites.

In another embodiment, a method includes introducing a delivery deviceat a location in a blood vessel and advancing the delivery device adistance into a wall (including entirely through the wall) of the bloodvessel to a treatment site. After the introduction of the deliverydevice, the method contemplates introducing an agent and a gel, such asa bioerodable gel, at the treatment site. Again, the treatment agent andthe bioerodable gel may be introduced simultaneously or sequentially asdescribed above.

In yet another embodiment, a kit (e.g., a pre-manufactured package) isdisclosed. A suitable kit includes a treatment agent and a compoundhaving a property that forms a bioerodable gel within a mammalian host.The kit may be suitable, in one example, in the methods described above.

In a further embodiment, an apparatus is disclosed. In one embodiment,the apparatus includes a first annular member having a first lumendisposed about a length of the first annular member, and a secondannular member coupled to the first annular member having a second lumendisposed about a length of the second annular member, whereincollectively the first annular member and the second annular member havea diameter suitable for placement at a treatment site within a mammalianbody. Representatively, distal ends of the first annular member and thesecond annular member are positioned with respect to one another toallow a combining of treatment agents introduced through each of thefirst annular member and the second annular member to allow a combiningof treatment agents at the treatment site. Such an apparatus isparticularly suitable for delivering a multi-component gel material(i.e., individual components through respective annular members) thatforms a bioerodable gel within a mammalian host.

BRIEF DESCRIPTION OF THE DRAWINGS

The features, aspects, and advantages of the invention will become morethoroughly apparent from the following detailed description, appendedclaims, and accompanying drawings in which:

FIG. 1 shows a cross-sectional side view of an embodiment of a substancedelivery apparatus including a single delivery device having both atreatment agent and a compound that forms a bioerodable gel in amammalian host within the delivery apparatus.

FIG. 2 shows a cross-sectional side view of a second embodiment of adelivery apparatus having both a treatment agent and a compound that mayform a bioerodable gel in a mammalian host.

FIG. 3 illustrates a simplified, cross-sectional side view of anembodiment of a substance delivery apparatus in the form of a catheterassembly including linear-aligned delivery lumens for a treatment agentand a compound that forms a bioerodable gel within a mammalian host.

FIG. 4 shows a cross-sectional front view of a distal end of thedelivery apparatus of FIG. 3.

FIG. 5 shows a cross-sectional side view of a distal portion of a secondembodiment of a substance delivery apparatus having a co-axialconfiguration for the delivery of the treatment agent and a compoundthat forms a gel within a mammalian host.

FIG. 6 shows a cross-sectional front view of a distal end of thedelivery apparatus of FIG. 5.

FIG. 7 shows a cross-sectional side view of a distal portion of a secondembodiment of a substance delivery apparatus having a co-axialconfiguration for the delivery of the treatment agent and a compoundthat forms a gel within a mammalian host.

FIG. 8 schematically illustrates a coronary artery network with acatheter assembly introduced therein.

DETAILED DESCRIPTION

In connection with the description of the various embodiments, thefollowing definitions are utilized:

“Therapeutic angiogenesis” refers to the processes of causing orinducing angiogenesis and arteriogenesis.

“Angiogenesis” is the promotion or causation of the formation of newblood vessels in the ischemic region.

“Arteriogenesis” is the enlargement of pre-existing collateral vessels.The collateral vessels allow blood to flow from a well-perfused regionof the vessel into the ischemic region.

“Ischemia” is a condition where oxygen demand of the tissue is not metdue to localized reduction in blood flow caused by narrowing orocclusion of one or more vessels. Narrowing of arteries such as coronaryarteries or their branches, is most often caused by thrombosis or viadeposits of fat, connective tissue, calcification of the walls, orrestenosis due to abnormal migration and proliferation of smooth musclecells.

“Occlusion” is the total or partial obstruction of blood flow through avessel.

“Treatment agent” includes medicaments such as a drug used in theprevention, alleviation, or cure of disease or injury, including, butnot limited to, agents directed to specific cellular binding sites(e.g., receptor binding treatment agents) and agents that induceinflammation.

“Specific binding treatment agent” or “receptor binding treatment agent”includes a protein or small molecule that will induce and/or modulate atherapeutic angiogenic response through interaction with a specificbinding sites (e.g., a binding within a cell or on a cell surface).Representative treatment agents include, but are not limited to,vascular endothelial growth factor (VEGF) in any of its multipleisoforms, fibroblast growth factors, monocyte chemoattractant protein 1(MCP-1), transforming growth factor beta (TGF-beta) in any of itsmultiple isoforms, transforming growth factor alpha (TGF-alpha), lipidfactors, hypoxia-inducible factor 1-alpha (HIF-1-alpha), PR39, DEL 1,nicotine, insulin-like growth factors, placental growth factor (PlGF),hepatocyte growth factor (HGF), estrogen, follistatin, proliferin,prostaglandin E1, prostaglandin E2, cytokines, tumor necrosis factor(TNF-alpha), erythropoietin, granulocyte colony-stimulating factor(G-CSF), granulocyte macrophage colony-stimulating factor (GM-CSF),angiogenin, hormones, and genes that encode such substances.

“Non-specific treatment agent” includes various agents that induceinflammation. Examples include bioresorbable inorganic compounds such assol gel particles and calcium phosphate glass comprising iron; fibrin,gelatin, low molecular weight hyaluronic acid, and chitin; bacterialpolysaccharides; and metals.

In the embodiments described herein, a substance delivery device and amethod for delivering a substance are disclosed. The delivery device andmethod described are particularly suitable, but not limited to, localdrug delivery in which a treatment agent composition (possibly includingmultiple treatment agents and/or a sustained-release composition) isintroduced via needle delivery to a treatment site within a mammalianhost. A kit of a treatment agent composition is also described. Onesuitable application for a delivery device is that of a catheter device,including a needle delivery system. Suitable therapies include, but arenot limited to, delivery of drugs for the treatment of arterialrestenosis, therapeutic angiogenesis, or cancer treatment drugs/agents.

Various apparati (devices) and methods described herein can be used as astand-alone injection needle/catheter during a surgical procedure suchas an open heart surgery (e.g., Cabbage Coronary Bypass Graft (CABG))procedure in which areas of the heart may be treated with, for example,growth factors, for affecting therapeutic angiogenesis, or incorporatedinto a catheter-based system to access locations that are commonly usedin percutaneous translumenal coronary artery (PTCA) procedures. Theapparati (devices) and methods may similarly be used in other surgicalprocedures such as cancer-related procedures (e.g., brain, abdomen, orcolon cancer procedures or surgeries). Additionally, various apparati(devices) and methods described herein can be used in conjunction withvarious catheter-related or endoscopy procedures that generally requireminimal invasiveness to deliver a specific drug or growth factor intotissue. Examples of such procedures include, but are not limited to,orthoscopic surgery for joints (e.g., knee), laparoscopic surgery forthe abdomen, and thoroscopic procedures related to chest injuries ortreatments.

One concern of introducing any treatment agent composition, whetheradjacent a blood vessel to affect therapeutic angiogenesis, adjacent atumor to inhibit tumor growth, or to induce or stimulate collagen growthin orthoscopic procedures, is that the composition remain (at leastpartially) at the treatment site for a desired treatment duration (or aportion of the treatment duration). In this manner, an accurate dosagemay be placed at a treatment site with reduced concern that thetreatment agent will disperse, perhaps with serious consequences.

In one embodiment, a composition and technique for retaining a treatmentagent at a treatment site (injection site) is described. In oneembodiment, a treatment agent and a bioerodable gel are introduced at atreatment site (e.g., an injection site). The bioerodable gel may beintroduced prior to, after, or simultaneously with the treatment agent.In one preferred embodiment, the bioerodable gel acts to retain thetreatment agent at the treatment site by, representatively, sealing thetreatment site or sealing the treatment agent at the treatment site. Theuse of a bioerodable gel with a treatment agent can reduce the amount oftreatment agent backflow from the injection site as well as reduce theload requirement of the treatment agent at the treatment site. Forexample, a bioerodable gel can decrease the local pressure therebyfurther resulting in backflow reduction.

In the area of cardiovascular treatment therapies, the treatment agentmay be a treatment agent that affects (e.g., induces and/or modulates)therapeutic angiogenesis. Suitable therapeutic angiogenesis treatmentagents include, but are not limited to, one or more of a specificbinding treatment agent. The treatment agent may further include or beincluded in a sustained-release matrix that delays the release of thetreatment agent over a period of time (such as over several hours toseveral days). Suitable sustained-release matrix material fortherapeutic angiogenesis treatment agents include, but are not limitedto, poly(L-lactide), poly(D,L-lactide), poly(glycolide), andpoly(lactide-co-glycolide) (PLGA) compositions. Another suitabletreatment agent is a non-specific treatment agent such as one that mayinduce inflammation. Reducing the backflow on introduction of thetreatment agent through the use of a gel may inhibit possiblethrombogenic effects of a treatment agent that induces inflammation.Although cardiovascular treatment agents are described, it isappreciated that other treatment agents are also contemplated, with onelimit being those treatment agents that are compatible with abioerodable gel material.

In one embodiment, particularly in the case of cardiovascular treatmenttherapies, the bioerodable gel material is selected to have a propertythat is non-thrombogenic. Suitable materials include material such aspolyphosphoester gels, such as a polyphosphoester with a low glasstransition temperature (e.g., POLIHEXOFATE™ polymer, commerciallyavailable from Guilford Pharmaceuticals of Baltimore, Md. (a copolymerof 1,4-cyclohexanedimethanol and n-hexylphosphate). Another suitablebioerodable gel is a gel formed from a moderately high glass transitiontemperature by a resolvable polymer that is plasticized in apharmaceutical water solvent, such as glucofurol to form the gel. Inthis latter case, the solvent is selected to be rapidly absorbed by thebody leaving the bioerodable material at the injection site. Otherpolymer materials include poly(glycolic lactic) acid (PLGA),caprolactone, and cyanoacrylate polymers. A third bioerodable gelmaterial is one that is formed by a combination (e.g., mixing,contacting, reacting) of two or more components. One example is analginate (alginic acid) and calcium chloride that combine to form a gelon contact within a mammalian host.

Accordingly, in one embodiment, a technique is described for introducinga treatment agent at a location in a mammalian host. Specifically, thetechnique comprises utilizing a delivery device for introducing atreatment agent and a compound that forms a bioerodable gel at atreatment site so as to increase the retention of the treatment agent atthe treatment site.

Referring now to the drawings, wherein similar parts are identified bylike reference numerals, FIG. 1 illustrates a cross-sectional side viewof one embodiment of a delivery device or apparatus. In general,delivery assembly 100 provides an apparatus for delivering a substance,such as a treatment agent or a combination of treatment agents and acomposition that forms a bioerodable gel in a mammalian host, to orthrough a desired area of a blood vessel (a physiological lumen) ortissue in order to treat a localized area of the blood vessel or totreat a localized area of tissue, possibly located adjacent to the bloodvessel. Delivery assembly 100 is intended to broadly include any medicaldevice designed for insertion into a blood vessel or physiological lumento permit introduction (e.g., injection) of a treatment agent.

Referring to FIG. 1, delivery assembly 100, in one embodiment, may be inthe form of a catheter delivery device that includes delivery lumen 110that may be formed in a larger catheter body (not shown). The largercatheter body may include one or more lumens to accommodate, forexample, a guidewire, an inflation balloon, and/or an imaging device.Further, such a catheter body may accommodate one or more deliverylumens, such as delivery lumen 110. Delivery lumen 110, in this example,extends between distal portion 105 and proximal portion 108 of deliveryassembly 100. Delivery lumen 110 can be made from any suitable material,such as polymers and co-polymers of polyamides, polyolefins,polyurethanes, and the like.

In one embodiment, delivery assembly 100 includes needle 120 movablydisposed within delivery lumen 110. Needle 120 is, for example, astainless steel hypotube that extends a length of the delivery assembly.Needle 120 includes a lumen with an inside diameter of,representatively, 0.16 inches (0.40 centimeters). In one example for aretractable needle catheter, needle 120 has a length on the order of 40inches (1.6 meters) from distal portion 105 to proximal portion 108. Atan end of proximal portion 108 is adapter 160 of, for example, a femaleluer housing.

Referring to distal portion 105 of delivery assembly 100, there is shownneedle 120 having treatment agent 122 disposed at or near its tip (tip121). In one example, treatment agent 122 is a material selected for itsability to affect therapeutic angiogenesis.

Disposed proximally (as viewed) to treatment agent 122 in needle 120 isgel material 124 that has a property such that it will form abioerodable gel when placed at a treatment site (e.g., in the wall of ablood vessel, in a periadventitial space, in an area radially outwardfrom a periadventitial space, etc.). Suitable materials for gel materialinclude, but are not limited to, the polyphosphoester gels andbioresorbable polymers (possibly dissolved in a solvent), such as PLGA,caprolactone or cyanoacrylate polymers referenced above.

One technique to load treatment agent 122 and gel material 124 into acatheter delivery device is by creating an area (volume) of reducedpressure in needle 120 by, for example, a syringe bore. First, distalportion 105 is placed in a solution having a selected concentration ofgel material 124, such as on the order of about 11 microliters(approximately 3-4 milligrams of polymer or 25 weight percent). Througha pressure differential, a desired amount of gel material 124 is takenup by needle 120.

Following the loading of gel material 124, needle 120 (distal portion105 of needle 120) is placed in a solution comprising a selectedconcentration of treatment agent 122 which, as is appreciated, will varywith the particular treatment and/or treatment agent. Again by a reducedpressure in needle 120, a desired amount of a treatment agent is takenup by needle 120.

In certain instances, it may be desired to combine the treatment agentand the gel material into a single composition and introduce the singlecomposition to a treatment site. Such an instance may be one where thecombination (e.g., mixing) of the gel material and the treatment agentdoes not inhibit (or minimally inhibits) the properties of the treatmentagent. One example in the context of cardiovascular treatment therapiesis a treatment agent that affects therapeutic angiogenesis by inducinginflammation, such as a metal (e.g., Au). It is appreciated in suchinstances that a solution composition of a gel material and a treatmentagent may be loaded into needle 120 by a pressure differential asdescribed or may be introduced through adaptor 160 (such as through aneedle luer).

Once loaded, such as described above, treatment agent 122 and gelmaterial 124 may be introduced according to known substance deliverytechniques such as by advancing tip 121 of needle 120 into tissue (e.g.,a wall of a blood vessel) and delivering the treatment agent and gelmaterial through back pressure (e.g., pressure applied at proximalportion 108, such as by a needle luer). Needle 120 may form a wound(wound opening) in tissue at the treatment site. The introduction of gelmaterial 124 following treatment agent 122 will tend to contain (retain)treatment agent 122 within the wound opening, thus reducing backflow.

FIG. 2 shows an alternative loading arrangement within needle 120. Inthis embodiment, treatment agent 122 is disposed between gel material.Again, each of the materials may be loaded in needle 120 throughpressure differential techniques. One order is loading gel material 124,followed by treatment agent 122, followed by gel material 126.

The configuration shown in FIG. 2 of treatment agent 122 disposedbetween gel material 124 and gel material 126 may be used,representatively, in a situation where it is desired to retain thetreatment agent within needle 120 until delivery (e.g., to prevent theloss of a portion of treatment agent 122 prior to delivery at atreatment site within a mammalian host).

FIG. 1 and FIG. 2 describe embodiments of techniques for introducing atreatment agent and a gel material, such as a bioerodable gel material,to a treatment site within a mammalian host (e.g., human). Suchembodiments are particularly suitable for use with gel material that maybe introduced in a single composition either as a gel (e.g., dispersedin solvent) or to form a gel within a mammalian host. FIG. 3 presents anembodiment of an apparatus that may be used to introduce a material thatis a combination of two materials that, when combined in a mammalianhost, form a bioerodable gel. One example of such a gel material is analginate and calcium chloride.

FIG. 3 presents delivery assembly 300 of, for example, acatheter-compatible device or apparatus. Delivery assembly 300 includesdelivery lumen 310 of, for example, a polymer material that may beformed in a larger catheter body (not shown). The larger catheter bodymay include one or more other lumens to accommodate, for example, anadditional delivery device lumen, a guidewire an inflation balloon,and/or imaging device. Delivery lumen 310, in this example, extendsbetween distal portion 305 and proximal end 308 of delivery assembly300.

In one embodiment, delivery assembly 300 includes main needle 320disposed within delivery lumen 330. Main needle 320 is movably disposedwithin delivery lumen 330. Main needle 320 is, for example, a stainlesssteel hypotube that extends a length of the delivery assembly. Mainneedle 320 includes a lumen with an inside diameter of, for example,0.08 inches (0.20 centimeters). In one example for a retractable needlecatheter, main needle 320 has a needle length on the order of 40 inches(1.6 meters) from distal portion 305 to proximal portion 308. Deliverylumen 310 also includes separate, possibly smaller diameter, auxiliarylumen 325 extending, in this example, co-linearly along the length ofthe catheter (from a distal portion 305 to proximal portion 308).Auxiliary lumen 325 is, for example, a polymer tubing of a suitablematerial (e.g., polyamides, polyolefins, polyurethanes, etc.). At distalportion 305, auxiliary lumen 325 is terminated to auxiliary needle end345 co-linearly aligned with a delivery end of needle 320. Auxiliarylumen 325 may be terminated to auxiliary needle end 345 with aradiation-curable adhesive, such as an ultraviolet curable adhesive.Auxiliary needle end 345 is, for example, a stainless steel hypotubethat is joined co-linearly to the end of main needle 320 by, forexample, solder (illustrated as joint 350B). Auxiliary needle end 345has a length on the order of about 0.08 inches (0.20 centimeters). FIG.4 shows a cross-sectional front view through line A-A′ of deliveryassembly 300. FIG. 4 shows main needle 320 and auxiliary needle 345 in aco-linear alignment.

Referring to FIG. 3, at proximal portion 308, auxiliary lumen 325 isterminated to auxiliary side arm 330. Auxiliary side arm 330 includes aportion extending co-linearly with main needle 320. Auxiliary side arm330 is, for example, a stainless steel hypotube material that may besoldered to main needle 320 (illustrated as joint 350A). Auxiliary sidearm 330 has a co-linear length on the order of about, in one example,1.2 inches (3 centimeters).

The proximal end of main needle 320 includes adaptor 360 foraccommodating a substance delivery device (e.g., a substance of atreatment agent or bioerodable gel material). Adaptor 360 is, forexample, a molded female luer housing. Similarly, a proximal end ofauxiliary side arm 330 includes adaptor 340 to accommodate a substancedelivery device (e.g., a female luer housing).

The design configuration described above with respect to FIG. 3 issuitable for introducing a bioerodable gel into two parts form. Forexample, a gel formed by a combination (mixing, contact, etc.) of analginate and calcium chloride. Representatively, a 3.5 percent of analginate solution may be introduced by a one cubic centimeters syringeat adaptor 360 through main needle 320. At the same time or shortlybefore or after, a solution of calcium chloride may be introduced with aone cubic centimeter syringe at adaptor 340. When the alginate andcalcium chloride combine at the exit of delivery assembly 300 (at atreatment site), the materials combine (mix, contact) to form abioerodable gel. One example of a suitable amount of two material gelcomponents for use in a cardiovascular treatment therapy isapproximately 200 microliters of alginate solution and one millilitercalcium chloride. Excess calcium chloride may flush through the host asa saline solution. In one embodiment, a desired amount of a treatmentagent may be introduced with the alginate solution.

FIG. 5 shows a second embodiment of a delivery assembly for delivering atwo part composition to a treatment site through a needle. In oneembodiment, the two part composition may be components that collectivelyform a bioerodable gel once inside a mammalian host.

FIG. 5 illustrates a co-axial alignment for delivering a two partcomposition to a treatment site. In this example, delivery assembly 400includes delivery lumen 410 to accommodate any co-axial needleconfiguration. Delivery lumen 410 extends, for example, the length ofthe catheter assembly, from a distal portion to a proximal portion. Inthe embodiment illustrated in FIG. 5, only the distal portion ofdelivery assembly 400 is illustrated. The proximal portion may besimilar to that described above with respect to FIG. 3 (e.g., separateports for introducing separate compositions into a single deliverylumen).

Referring to FIG. 5, delivery assembly 400 includes main needle portion420 of, for example, a stainless steel hypotube material having a lumendiameter on the order of 0.08 inches (0.20 centimeters) and extendingthe length of the delivery assembly (from distal portion to proximalportion). Surrounding main needle portion 420, in this example, isauxiliary needle portion 445. Auxiliary needle portion 445 has a largerdiameter than the diameter of main needle portion 220 such that anopening or a lumen is created between main needle portion 420 andauxiliary portion 445 to allow the introduction of a materialtherethrough. An exemplary interior diameter of auxiliary needle portion445 is on the order of 0.16 inches (0.40 centimeters).

Auxiliary needle portion 445 is, for example, stainless steel hypotubematerial that may be coupled to main needle portion 420 through supportvanes 455 (e.g., by laser welding support vanes to auxiliary needleportion 445 and main needle portion 420). Auxiliary needle portion 445may extends the entire length of needle assembly 400 (i.e., from distalportion to proximal portion) or may comprise only a tip or end portionof, for example, 0.02 to 0.08 inches (0.05 to 0.2 centimeters). In thelatter case, auxiliary lumen 425 of, for example, a polymer material mayextend through delivery assembly 400 and be terminated to auxiliaryneedle portion 445 with, for example, a radiation-curable adhesive.

FIG. 5 shows main needle portion 420 having an end (a distal end)portion extending beyond auxiliary needle portion 445. In this manner,the distal end of delivery assembly 420 may be configured as an angletip, with an angle α, of between, for example, 15 degrees to 45 degreesto allow the penetration of tissue with the end of delivery device 400.The angle α extends around the assembly.

FIG. 6 shows a cross-sectional front view of delivery assembly 400through line B-B′ of FIG. 5. FIG. 6 shows main needle portion 420co-axially surrounded by auxiliary needle portion 445 with support vanes455 extending between main needle portion 420 and auxiliary needleportion 445.

In an embodiment where a two part composition of an alginate and calciumchloride is introduced to form a bioerodable gel, the low viscositymedium (calcium chloride) may be introduced (injected) through the outerannular portion (defined by the lumen between main needle portion 420and auxiliary needle portion 445). The higher viscosity medium calciumchloride may be introduced through the lumen defined by main needleportion 420.

FIG. 7 shows a cross-sectional side view of a third embodiment of adelivery device for delivering a multi-component material to a treatmentsite. The configuration shown in FIG. 7 is also a co-axial arrangement(similar to FIGS. 5 and 6). Delivery assembly 500 includes deliverylumen 510, main needle portion 520, auxiliary portion 545, co-axiallysurrounding main needle portion 520. In this embodiment, main needleportion 520 extends, representatively, the length of delivery assembly500 (from distal portion to proximal portion). Auxiliary needle portion545 is a tip portion of, for example, a stainless steel hypotubematerial that may be coupled to main needle portion 520 by support vanes555. Auxiliary lumen 525 of, for example, a polymer material may extendthe length of delivery assembly 500 and be terminated at auxiliaryneedle portion 545 with an adhesive (e.g., a radiation-curableadhesive).

In the embodiment shown in FIG. 7, the distal end of delivery assembly500 includes an angle tip formed by main needle portion 520 andauxiliary needle portion 545. From this example, the tip is a singleangle tip, with an end angle, α, on the order of 15 degrees to 45degrees. In this manner, the angle tip allows for insertion into tissue.

The catheter assemblies described with reference to FIGS. 1-7 may beused to introduce a treatment agent and a gel such as described above ata desired location. FIG. 8 illustrates one technique.

FIG. 8 illustrates components of a coronary artery network. In thissimplified example, vascular 650 includes left anterior descendingartery (LAD) 660, left circumflex artery (LCX) 670 and right coronaryartery (RCA) 680. Occlusion 685 is shown in LCX 670. Occlusion 685 maylimit the amount of oxygenated blood flow through LCX 670 resulting inischemia in the tissues distal (downstream) to the occlusion. To improvethe function of the artery network, it is generally desired to eitherremove occlusion 685 (for example, through an angioplasty procedure),bypass occlusion 685 or induce therapeutic angiogenesis to make-up forthe constriction in the ischemic region.

With reference to FIG. 8, in a one procedure, guidewire 618 isintroduced into, for example, the arterial system of the patient (e.g.,through the femoral artery) until the distal end of guidewire 618 isupstream of a narrowed lumen of the blood vessel (e.g., upstream ofocclusion 685). Delivery assembly 600 (in this example, a ballooncatheter device) is mounted on the proximal end of guidewire 618 andadvanced over guidewire 618 via lumen 616 until positioned as desired.In the example shown in FIG. 8, delivery assembly 600 is positioned sothat catheter balloon 625 and a delivery lumen 640 (see, e.g., deliverylumen 110 (FIG. 1); delivery lumen 310 (FIG. 3); delivery lumen 410(FIG. 5); delivery lumen 510 (FIG. 7)) are upstream of the narrowedlumen of LCX 670. Angiographic or fluoroscopic techniques may be used toplace delivery assembly 600. Once catheter balloon 625 is placed, atreatment site of the blood vessel may be identified by further imagingtechniques, including but not limited to, optical coherence tomography,ultrasonic, or magnetic resonance techniques. An example of an opticalimaging technique is described in co-pending commonly-assigned U.S.patent application Ser. No. 10/011,071 where catheter balloon 630 issubject to low inflation pressure and guidewire 618 is removed andreplaced in one embodiment with an optical fiber. In the catheterassembly shown in FIG. 8, the imaging portion of an imaging device(e.g., OCT, ultrasonic, etc.) may be within the imaging lumen as thecatheter is positioned. Once positioned, in this case upstream ofocclusion 685, the imaging assembly is utilized to view the blood vesseland identify the various layers of the blood vessel.

The imaging assembly may provide viewable information about thethickness or boundary of the intimal layer 672, media layer 674, andadventitial layer 676 of LCX 670. LCX 670 is viewed and the layerboundary is identified or a thickness of a portion of the blood vesselwall is imaged (and possibly measured). The treatment site may beidentified based on the imaging (and possibly measuring). In oneexample, the treatment site is a peri-adventitial site (e.g., site 678)adjacent to LCX 670.

After identifying a treatment site, catheter balloon 625 is dilated asshown in FIG. 8 by, for example, delivering a liquid or gas to catheterballoon 625 through inflation lumen 622. Delivery lumen 640, in thisexample, is coupled to a proximate tapered wall of catheter balloon 620such that, as catheter balloon 620 is inflated, delivery lumen 640 movesproximate to or contacts the blood vessel wall adjacent to the treatmentsite. The delivery assembly (device) described is similar in certainrespects to the assembly (device) described in commonly-owned U.S.patent application Ser. No. 09/746,498 (filed Dec. 21, 2000) titled“Directional Needle Injection Drug Delivery Device,” of Chow, et al.,that is incorporated herein by reference. Needle 630 is then advanced adistance into the wall of the blood vessel. A real time image may beused to advance needle 620. Alternatively, the advancement may be basedon a measurement of the blood vessel wall or layer boundary derived froman optical image. Needle 620 may be, for example, similar to designsdescribed above with reference to FIGS. 1 and 2 (needle 120).Alternatively, needle 620 may be a dual needle assembly similar todelivery assembly 300 described with reference to FIGS. 3 and 4 (e.g.,main needle 320 and auxiliary lumen 325/auxiliary needle 345). As afurther alternative, needle 620 may be similar to the embodimentdescribed with reference to FIGS. 5 and 6 (main needle portion 420 andauxiliary needle portion 445) or FIG. 7 (main needle portion 520 andauxiliary needle portion 545).

In the embodiment shown in FIG. 8, needle 620 is advanced through thewall of LCX 670 to peri-adventitial site 690. Once in position, atreatment agent and gel are introduced through needle 620 to thetreatment site (e.g., peri-adventitial site 690).

In the preceding detailed description, specific embodiments arepresented. Those embodiments include apparati (devices) and methods forintroducing a treatment agent and a gel at a treatment site within amammalian body. Cardiovascular treatment therapies in particular arehighlighted. It will, however, be evident that various modifications andchanges may be made thereto without departing from the broader spiritand scope of the claims. For example, contemplated treatment therapiesinclude therapies, in addition to cardiovascular treatment therapies,where blood vessels or tissues are identified for localized treatmentagents in the context of surgery or other medical procedure. Thespecification and drawings are, accordingly, to be regarded in anillustrative rather than a restrictive sense.

1. A method comprising: introducing a treatment agent at a treatmentsite within a mammalian host; and introducing a bioerodable gel materialat the treatment site.
 2. The method of claim 1, wherein the treatmentagent and the gel material are introduced separately as a combination.3. The method of claim 1, wherein the gel material is a product of acombination of a first component and a second component and one of thefirst component and the second component comprises the treatment agent.4. The method of claim 1, wherein introducing the gel materialcomprises: introducing a delivery device having a first delivery portand a second separate delivery port, the first delivery port and thesecond delivery port arranged in one of a co-linear and a co-axialarrangement; and introducing the first component to the treatment sitethrough the first delivery port; and introducing the second component tothe treatment site through the second delivery port.
 5. The method ofclaim 4, wherein the treatment site is associated with a blood vessel.6. The method of claim 5, wherein introducing the treatment agentcomprises: advancing the delivery device a distance into a wall of theblood vessel to the treatment site; and after advancing the deliverydevice, introducing the treatment agent through the delivery device. 7.The method of claim 6, wherein the treatment site comprises a location,with reference to a lumen of the blood vessel, beyond the medial layerof the blood vessel.
 8. The method of claim 6, wherein the treatmentsite comprises a periadventitial site.
 9. The method of claim 1, whereinintroducing the gel material follows the introduction of the treatmentagent.
 10. The method of claim 1, wherein introducing the gel materialprecedes the introduction of the treatment agent.
 11. The method ofclaim 4, wherein the treatment site is selected from the groupconsisting of a thoroscopic surgery site, an orthoscopic surgery site,and a laparoscopic surgery site.
 12. A method comprising: positioning adelivery device at a location in a blood vessel; advancing the deliverydevice a distance into a wall of the blood vessel to a treatment site;and after advancing the delivery device, introducing a treatment agentand a gel material at the treatment site.
 13. The method of claim 12,wherein the treatment agent and the gel material are introduced as acombination.
 14. The method of claim 13, wherein the gel material is aproduct of a combination of a first component and a second component andone of the first component and the second component comprises thetreatment agent.
 15. The method of claim 14, wherein introducing the gelmaterial comprises: introducing a delivery device having a firstdelivery port and a second separate delivery port, the first deliveryport and the second delivery port arranged in one of a co-linear and aco-axial arrangement; and introducing the first component to thetreatment site through the first delivery port; and introducing thesecond component to the treatment site through the second delivery port.16. The method of claim 15, wherein the treatment site is associatedwith a blood vessel.
 17. The method of claim 16, wherein introducing thetreatment agent comprises: advancing the delivery device a distance intoa wall of the blood vessel to the treatment site; and after advancingthe delivery device, introducing the treatment agent through thedelivery device.
 18. The method of claim 17, wherein the treatment sitecomprises a location, with reference to a lumen of the blood vessel,beyond the medial layer of the blood vessel.
 19. The method of claim 18,wherein the treatment site comprises a periadventitial site.
 20. Themethod of claim 12, wherein introducing the gel material follows theintroduction of the treatment agent.
 21. The method of claim 12, whereinintroducing the gel material precedes the introduction of the treatmentagent.